Endocrine therapy represents a mainstay of effective, minimally toxic, palliative treatment for metastatic breast cancer. As a standard palliative treatment of non-operable mammary carcinomas as well as for adjuvant therapy after primary treatment of mammary carcinomas predominantly the antiestrogen tamoxifen is used. However, tamoxifen cannot cure breast cancer. Thus, for secondary therapy progestins or aromatase inhibitors are commonly used. In premenopausal women ovariectomy, tamoxifen and LHRH (luteinizing hormone releasing hormone) analogs achieve comparable results (H. T. Mouridson et al., Eur. J. Cancer Clin. Oncol., 24, pp. 99-105, 1988).
Although tamoxifen is widely used for adjuvant therapy of breast cancer, its use as a chemopreventive agent is problematic, because it has been shown that the treatment results in an increase in the incidence of endometrial cancers (I. N. White, Carcinogenesis, 20(7): 1153-60, 1999).
Antiprogestins represent a relatively new and promising class of therapeutic agents that could have significant impact on breast cancer treatment. Although antiprogestins were originally created with regard to medicinal non-surgical termination of pregnancy (EP 129 499), certain antiprogestins have recently gained importance in the endocrine therapy of those breast cancers involving receptors for progesterone (T. Maudelonde et al., in: J. G. M. Klijn et al., Hormonal Manipulation of Cancer: Peptides, Growth Factors and New (Anti) Steroidal Agents, Raven Press, New York, 1987, pp. 55-59). This new strategy in endocrine therapy is based on the antitumor activity of antiprogestins in progesterone receptor-positive human breast cancer cell lines in vitro and in several hormone-dependent mammary tumors of the mouse and rat in vivo. In particular, the antitumor mechanism of the antiprogestins onapristone and mifepristone (RU 486) was investigated using the hormone-dependent MXT mammary tumor model of the mouse as well as the DMBA- and the NMU-induced mammary tumor models of the rat (M. R. Schneider et al., Eur. J. Cancer Clin. Oncol., Vol. 25, No. 4, pp. 691-701, 1989; H. Michna et al., Breast Cancer Research and Treatment 14:275-288, 1989; H. Michna, J. Steroid. Biochem. Vol. 34, Nos 1-6, pp. 447-453, 1989). However, due to low activity and adverse side effects involved with e.g. mifepristone this compound could not be recommended as a single agent in the management of breast cancer (D. Perrault et al., J Clini. Oncol. 1996 October 14(10), pp. 2709-2712).
Antiprogestin compounds are suitable for initiating abortions and thus for use in postcoital fertility control, as contraceptives for women (WO-A 93/23020, WO-A 93/21927) and further for the treatment of hormone irregularities, for initiating menstruation and for initiating labor. Further indications are in the field of hormone substitution therapy (WO-A 94/18983), the treatment of afflictions related to dysmenorrhea and the treatment of endometriosis (EP-A 0 266 303) as well as myomas.
17 α-fluoroalkylsteroids having strong antiprogestin activity as well as methods for producing them are described in WO 98/34947.
Antiprogestins of the prior art tested or used previously due to their antitumor activity frequently exhibited certain disadvantages.
For example, despite the fact that prior art antiprogestins exhibited antigestagenic activity, these compounds were not suitable treatments for hormone-dependent diseases such as breast cancer. In particular, prior art compounds were associated with side effects, e.g. mifepristone exhibits strong antiglucocorticoid side effects (cf. L. M. Kettel et al., Fertil. Steril. 1991 September, 56(3), pp. 402-407; X. Bertagna, Psychoneuroendocrinology 1997; 22 Suppl. 1, pp. 51-55) and besides it showed only moderate activity in clinical trials (see again D. Perrault et al., J. Clin. Oncol. 1996 October, 14(10), pp. 2709-2712). Regarding side effects of other hormone-based therapies, as already mentioned above, tamoxifen administration can result in an increase in the incidence of endometrial cancers (I. N. White, Carcinogenesis, 20(7):1153-60, 1999).
Another problem with prior art antiprogestins was poor bioavailability when administered orally. Thus, they generally had to be administered in high doses, giving rise to possible unfavorable side effects. Moreover, oral administration is desirable with respect to patient convenience and compliance.
Furthermore, there is still a need for compounds that are active not only in the treatment, but also in the prophylaxis of breast cancer and other hormone-dependent diseases. The increased incidence of endometrial cancer associated with tamoxifen tends to show that this compound is unsuitable for prophylaxis treatment of healthy women, and no other suitable compounds are available (cf. L. Bergman et al., The Lancet, Vol. 356, Sep. 9, 2000; 881-887).